REVIEW published: 02 February 2021 doi: 10.3389/fphar.2020.618836

The Potential of Cryptophyte Algae in Biomedical and Pharmaceutical Applications

Maryam Abidizadegan 1*, Elina Peltomaa 2 and Jaanika Blomster 3

1Environmental Laboratory, Faculty of Biological and Environmental Sciences, University of Helsinki, Lahti, Finland, 2Institute of Atmospheric and Earth System Research (INAR)/Forest Sciences, University of Helsinki, Helsinki, Finland, 3Ecosystems and Environment Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland

Microalgae produce a variety of bioactive components that provide benefits to human and animal health. Cryptophytes are one of the major groups of microalgae, with more than 20 genera comprised of 200 species. Recently, cryptophytes have attracted scientific attention because of their characteristics and biotechnological potential. For example, they are rich in a number of chemical compounds, such as fatty acids, carotenoids, phycobiliproteins and polysaccharides, which are mainly used for food, medicine, cosmetics and pharmaceuticals. This paper provides a review of studies that assess protective algal compounds and introduce cryptophytes as a remarkable source of bioactive components that may be usable in biomedical and pharmaceutical sciences.

Keywords: fatty acids, sterols, carotenoida, mycosporine-like amino acids, polysaccharides, phenolics, vitamins, cryptophytes Edited by: Banasri Hazra, Jadavpur University, India Reviewed by: INTRODUCTION Mingyao Gu, fi Shenzhen University, China In recent years, commercial and scienti c attention has remarkably boosted the interest in natural Ligia Salgueiro, products from aquatic organisms, especially algae - both macroscopic algae and microalgae. University of Coimbra, Portugal Microalgae are broadly considered as good sources of fiber, minerals, antioxidants, vitamins, *Correspondence: pigments, steroids, lectins, polysaccharides, proteins, polyunsaturated fatty acids and other lipids Maryam Abidizadegan (Blunt et al., 2012; Aditya et al., 2016). These products can be commercially used in a variety of Maryam.abidizadegan@Helsinki.fi applications, for example in human and animal nutrition, in cosmetics and beauty products, and for the synthesis of antibacterial, antiviral, antimicrobial and anticancer drugs (Cardozo et al., 2017; Specialty section: Rizwan et al., 2018). fi This article was submitted to The conversion of light energy into chemical energy by CO2 xation is ten times higher in Ethnopharmacology, microalgae than in terrestrial plants, making the production efficiency of microalgae outstanding. a section of the journal Currently, the commercial production of microalgae has been reported roughly 5,000 tons per Frontiers in Pharmacology year of dry matter (Raja et al., 2008). Almost 110 commercial products of microalgae are found in the Received: 19 October 2020 Asia-Pacific area (Sathasivam et al., 2019). Of the estimated 200,000–800,000 microalgal species, only Accepted: 31 December 2020 about 35,000 strains are scientifically described (Cheng and Ogden, 2011), only few of which are Published: 02 February 2021 commercially employed. Citation: Cryptophyte algae form one of the major groups of phytoplankton, with more than 20 genera Abidizadegan M, Peltomaa E and composed of 200 species (Clay et al., 2015). They are unicellular, eukaryotic algae generated from Blomster J (2021) The Potential of Cryptophyte Algae in Biomedical and secondary endosymbiosis between a single-cell eukaryote host and a red algal predecessor Pharmaceutical Applications. (Greenwold et al., 2019)(Figure 1). The red algal ancestor has provided the cryptophyte plastid, Front. Pharmacol. 11:618836. and the ancestors’ genome forms the nucleomorph found in the plastid (Figures 2A,B). Depending doi: 10.3389/fphar.2020.618836 on their accessory pigments, cryptophytes are bluish, reddish, brownish or green in color.

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Cryptophytes do not possess a cell wall, but like all chromophyte solar energy exploitation, and aquaculture (Lee et al., 2019). The algae, they have an extra pair of membranes around their plastids. aim of this review is to summarize the promising microalgal Active movements are enabled by two flagella (Figure 2). compounds, with special emphasis on compounds derived from Cryptophytes are significant primary producers in both cryptophyte algae. These compounds could be useful in freshwater and marine habitats, and proven to be a highly nutraceuticals and in medical and pharmaceutical applications important food source for secondary producers due to their for producing natural drugs and other biomedical materials. exceptionally good fatty acid, sterol and amino acid profiles and concentrations that meet the needs of consumers (Brett et al., 2009; Martin-Creuzburg and Von Elert, 2009; Clay METHODOLOGY et al., 2015; Peltomaa et al., 2017). Thus far, nine cryptomonads organelle genomes have been sequenced and Four databases, i.e. PubMed, Sciencedirect, MDPI and published, which includes three nucleomorph, one nuclear, ResearchGate, were used in the search for relevant studies. three plastid and two mitochondrial genomes (Douglas, 1992; Search words were: “cryptophytes,”“algal bioactive Kim et al., 2015). compounds,”“cryptophyte pigments,”“cryptophyte Growth rates of most cryptophytes are considered as fairly carbohydrates,”“cryptophyte vitamins,”“cryptophyte − slow (well below 0.8 div. day 1), and they may therefore be phytosterols,”“cryptophyte polyphenols” and “cryptophyte ignored in commercial terms. Nonetheless, in appropriate MAAs.” There was no time limitation because of the scarce environments some strains possess higher growth rates, e.g. literature about cryptophytes. Of the received hits only basic − 1.2 div. day 1 (Lewitus and Caron, 1990). Due to their small information on the bioactive compounds, and their applications cell size (below 500 µm3), the cell biomass of cryptophytes is low in medicine and pharmacology were selected to write this review in comparison with of many diatoms and dinoflagellates, which article. may give an incorrect impression of the gain of effective biomass: cryptophytes lack heavy cell wall structures made of silica or cellulose, and thus most of the entire biomass is useable. Further, BIOACTIVE COMPOUNDS OF cryptophyte cells can be broken and processed more easily than CRYPTOPHYTES diatoms or dinoflagellates for commercial applications (Scholz et al., 2014). Cryptophytes from the TPG (Teleaulax/Plagioselmis/ Fatty Acids Geminigera) and RHO (Rhodomonas/Rhinomonas/Storeatula) Fatty acids are carboxylic acids with long aliphatic chains, which clades have been suggested as possible species for are either branched or straight, and can be saturated or biotechnological purposes in the areas of health improvement, unsaturated. Depending on the number of double bonds, FAs are categorized as monounsaturated FAs (MUFAs, with one double bond), or polyunsaturated FAs (PUFAs, with ≥2

Figure 1 | Evolution of cryptophytes according to pigment, ultrastructure Figure 2 | (A): Cryptophyte cell structure. P, plastid; NM, nucleomorph; and molecular phylogenic data. Chl, chlorophyll; PBS, phycobilisome; LHC, MT, mitochondrion (adapted from Hoef-Emden 2008). (B): Photo of a light harvesting complex (adapted from Green 2001). cryptophyte Rhinomonas nottbecki n. sp. taken by Janne-Markus Rintala.

Frontiers in Pharmacology | www.frontiersin.org 2 February 2021 | Volume 11 | Article 618836 Abidizadegan et al. Biomedical Applications of Cryptophyte Algae double bonds). Moreover, PUFAs are classified as omega-3 (ω-3) development in infants (Bird et al., 2018). From the ω-6 fatty or omega-6 (ω-6) fatty acids based on the position of the first acids, gamma-linolenic acid (GLA, 18:3 ω-6) is an essential double bond from the methyl end. In algae, the fatty acid carbon fatty acid presenting anti-inflammatory properties. skeleton mostly varies from C12 to C24 with one or more double Arachidonic acid (AA) can be effective in controlling bonds. A wide range of FAs and their oxidized products of neurological diseases such as Alzheimer’sdisease(Rapoport nutritional and chemo-taxonomic importance are found in et al., 2007) and autism (Bell et al., 2004), and can play algae, but their FA profiles are species dependent, i.e. FA significant roles in muscle development - especially for production is genetically determined (Kumari et al., 2013). individuals practicing physical exercise (Standley et al., 2013). Omega-3 and omega-6 fatty acids – especially However, the proportion of ω-6FAsistoohighinthewestern eicosapentaenoic acid (EPA, 20:5 ω-3) and docosahexaenoic diet, which poses several negative health consequences. The balance acid (DHA, 22:6 ω-3) are vital for normal cell activities. of ω-6/ω-3 FA is important in reducing the risk for coronary heart However, most consumers, including humans, cannot disease, and is beneficial to bone health and skeletal growth synthesize these essential long-chain PUFAs (LCPUFAs) (Simopoulos, 2008). themselves, and their capability of bioconversion is very Thus far, fish have been the main source of essential LCPUFAs limited. Thus, EPA and DHA need to be obtained from the for humans. Alternative sustainable sources for the LCPUFAs are diet (Burdge and Calder, 2005). Due to their biologically essential necessary to fulfill the need of the growing human population, role, omega fatty acids have entered the biomedical and since the marine fishing industry has reached its maximal nutraceutical fields, where they are being used for treating production capacity. As fish do not have efficient enzymatic various ailments such as obesity, cardiovascular diseases mechanisms for the synthesis of LCPUFAs, they accumulate (CSD), arrhythmia, strokes, high blood pressure, dementia, these in their bodies through the consumption of microalgae, asthma, and improving renal diseases and rheumatoid arthritis which are the principal producers of the healthy FAs (Ghosh (Ryckebosch et al., 2012). For example, high consumption of EPA et al., 2015). Thus, microalgae which contain approximately 30% and DHA restricts the metabolites of arachidonic acid (AA, 20:4 of lipids are very attractive as natural replacements for fish and ω-6) and inhibits inflammation. In addition, a balanced ω-6/ω-3 fish oil food supplements for humans (Andrade et al., 2018). ratio is one of the most essential dietary agents to prevent obesity Moreover, fish oil is inappropriate for some people who have fish (Simopoulos, 2016). Omega fatty acids play an important role in allergies, for vegetarians, and for those who may dislike fish oil normal fetal brain development and growth of infants (Jubies due to its possible unpleasant odor or the concerns for lipid- et al., 2012). The amount of EPA and DHA in the bloodstream of soluble environmental pollutants (Cuellar-Bermudez et al., 2015). children with autistic spectrum disorders or attention deficit Thus, supplementary products made from microalgae can be hyperactivity disorder (ADHD) had been lower than in superior over the currently widely used fish oil (Ward and Singh, control children (Calder, 2018). Deficiency of ω-3 can lead to 2015). However, only certain microalgae can synthesize EPA and dry skin, fatigue, heart conditions, poor memory and even DHA and can therefore be used for commercial LCPUFA schizophrenia (Pawelczyk et al., 2016; Andrade et al., 2018). production. According to the study of (Sanchez-Villegas et al., 2018), One of the microalgal groups that are high in PUFA is moderate intake of omega-3 PUFA can effectively preserve cryptophytes. In fact, all cryptophytes regardless of the species against depression irrespective of the presence of have been shown to be rich in EPA (C20H30O2) or DHA ω cardiometabolic disturbances, sex differences or life-style (C22H32O2) and other -3 PUFAs, i.e. alpha-linolenic acid habits. Therefore, EPA supplementation is suggested as a vital (ALA, 18:3 ω-3, C18H30O2) and stearidonic acid (SDA, 18:4 ω-3, anti-depressant treatment. Supplementation studies using C18H28O2)(Table 1)(Barreira et al., 2015). However, compared omega-3 have indicated the decline in mortality due to fewer to marine cryptophytes, freshwater species contain less DHA sudden cardiac deaths from reduction of arrhythmogenesis (Martins et al., 2013; Appleton et al., 2015; Maki et al., 2017). TABLE 1 | Cryptophyte species with high amounts of ω-3: ALA (alpha-linolenic EPA functions as a precursor for substances like prostaglandin-3, acid), SDA (stearidonic acid), EPA (eicosapentaenoic acid) and DHA thromboxane-3, and leukotriene-5 group. Further, EPA takes (docosahexaenoic acid). part in our defense system against inflammation by neutralizing Species FA (% of total) the pro-inflammatory function of other similar molecules. Another remarkable merit of EPA is its ability to prevent clots ALA SDA EPA DHA from forming in the blood, which results in improvement of heart Chroomonas salina 10.8 30.3 12.9 7.1 health, blood circulation and decreased risk of thrombosis (Gray Cryptomonas sp. 25.1 30.7 12.0 6.6 and Bolland, 2014). DHA with antioxidant activities is the most Rhodomonas sp. 25.2 22.6 8.7 4.6 valuable fatty acid for brain health; it helps the cognition and Chroomonas mesostigmatica 13.5 17.4 20.5 1.7 fi Guillardia theta 56.7 25.5 19.9 3.0 connection between neurons, and has bene cial aspects related to Hemiselmis sp. 53.2 20.5 21.2 5.1 our mind including attention, imagination, memory, reasoning Proteomonas sulcata 58.5 16.2 12.7 12.6 and judgment (Andrade et al., 2018). When alpha-linolenic acid Storeatula major 41.9 32.1 16.0 10.0 (ALA, 18:3 ω-3) and linoleic acid (LA, 18:2 ω-6) values are less Teleaulax acuta 46.2 13.4 26.0 14.3 than 0.5% of energy, this can lead to impaired barrier function Teleaulax amphioxeia 43.3 20.5 23.6 12.7 and wound healing as well as poor neurological and visual (adapted from Barreira et al., 2015; Patil et al., 2007).

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(Patil et al., 2007). At the species level, for example, Chroomonas sterol biosynthetic pathways (Nes, 2011). Sterol compound mesostigmatica has been introduced as promising strain for EPA differs according to the algal strain, and can be modified by extraction, whereas Storeatula major has shown promise for both temperature, light intensity and growth phase. Together these EPA and DHA production (Peltomaa et al., 2018). In addition to features make microalgae a potential and promising source of ω-3 PUFAs, cryptophytes also produce ω-6 PUFAs, which are phytosterols for health benefits (Galasso et al., 2019). Since beneficial especially for dietary products (Huerlimann et al., phytosterols can act as secondary messengers, similar to 2010). hormones, they affect cellular processes including neurotransmission and development (Francavilla et al., 2010). Sterols Phytosterols derived from microalgae have been shown to have Sterols are an important family of lipids that are biosynthesized anti-cancer, anti-inflammatory, antioxidant or anti- by all eukaryotic organisms (Desmond and Gribaldo, 2009). cholesteroligenic (Hwang et al., 2014; Cabral and Klein, Cholesterol, the prominent sterol in animals, is scarcely found 2017), immunomodulatory (Caroprese et al., 2012), anti- in plants. Alternatively, plants are composed of certain types of diabetic (Lee et al., 2004) and antibacterial properties (Luo phytosterols, which are functionally and structurally similar to et al., 2015). Additionally, evidence suggests that phytosterols cholesterol (Hernandez-Ledesma and Herrero, 2014). Unlike offer protection against nervous system disorders like cholesterol, humans have to obtain phytosterols from their diet Alzheimer’s disease and autoimmune encephalomyelitis since they cannot produce them endogenously (Tasan et al., (Ahmed et al., 2015). The phytosterols derived from 2006). Up to now, higher plants have been the major industrial microalgae can decrease the dietary cholesterol absorption source of phytosterols (Fernandes and Cabral, 2007), but and thus prevent hypercholesterolemia (Chen et al., 2014; phytosterols are also found in algae (Hernandez-Ledesma Luo et al., 2015). By becoming incorporated into the cell and Herrero, 2014). Sterol distribution in microalgae presents membrane, phytosterols can alter the activity of some a large number of structures that reflectdistinctdifferencesin membrane-bound enzymes and the signal transduction in

TABLE 2 | Bioactivities of phytosterols derived from cryptophytes.

Identified phytosrerols Cryptophytes species Phytosterol content Biological activity (µg/mg dry weight)

Crinosterol Chroomonas mesostigmatica 0.93 Anti-aging Hemiselmis sp. 0.43 Rhodomonas salina 0.14 Storeatula major 0.24 Teleaulax amphioxeia 0.45 Brassicasterol Chroomonas mesostigmatica 0.02 Cholesterol Cryptomonas ovata — Lowering Rhodomonas minuta — Anti-aging Guillardia theta 0.31 Hemiselmis sp. 1.11 Proteomonas sulcata 0.71 Rhodomonas salina 0.84 Storeatula major 0.72 Teleaulax acuta 0.35 Stigmasterol Storeatula major — Thyroid-inhibitory Guillardia theta 0.36 Antioxidant Cryptomonas ovata — Hypoglycaemic Rhodomonas minuta — Cholesterol-lowering Anti-cancer Anti-inflammatory Anti-osteoarthritic Campesterol Cryptomonas marssonii — Cholesterol-lowering Anti-cancer Anti-angiogenic Antioxidant β-Sitosterol Cryptomonas marssonii — Anti-cancer Anti-inflammatory Analegesic activity Antihelminthic Antimutagenic

(adapted from Luo et al., 2015; Peltomaa et al., 2018).

Frontiers in Pharmacology | www.frontiersin.org 4 February 2021 | Volume 11 | Article 618836 Abidizadegan et al. Biomedical Applications of Cryptophyte Algae pathways that cause tumor growth (Lopes et al., 2013). Further, of transcription factors (Sathasivam and Ki, 2018). The use of algae-derived phytosterols have been shown to have anti- synthetic antioxidants in the European Union countries is under diabetic activity in diabetic rats, suggesting that they could strict regulation, because of their possible potential health risks. have potential in the prevention of type 2 diabetes in Thus, natural antioxidants can be used as safe alternatives in the humans (Lee et al., 2004). industry (Gouveia et al., 2010). The increasing interest for natural Five different phytosterols including crinosterol (C28H46O), and organic beauty products boosts the commercial potential for brassicasterol (C28H46O) (the major sterol in cryptophytes), carotenoids extracted from microalgae. β -sitosterol (C29H50O; BS) campesterol (C28H48O) and Cryptophytes have carotenoids that are useful in different fi stigmasterol (C29H48O) have been found in cryptophytes industries, speci cally in medicine and pharmacy. The major (Table 2)(Taipale et al., 2016; Peltomaa et al., 2017). BS carotenoid in cryptophytes is called alloxanthin (C5H4N4O2) possesses a skin conditioning influence used in anti-aging (Ansotegui et al., 2003; Cunningham et al., 2018)(Table 3), and cosmetic products, moisturizer, sunscreen and body wash is present e.g. in the marine cryptophytes Teleaulax acuta and (Han et al., 2014). BS also plays a crucial role in modulating Hemiselmis sp. (Seoane et al., 2005). Cryptophytes also contain α antioxidant enzymes and human estrogen receptor (Song et al., other kinds of carotenoids, including -carotene (C40H56) 2000), as well as in blood vessel formation, thus having wound (Table 3), crocoxanthin (C40H54O), monadoxanthin healing potential (Moon et al., 1999). Moreover, BS has been used (C40H54O2), cryptoxanthin (C40H56O) (Margulis and in the treatment of hyperlipidemia, and has antipyretic effects and Chapman, 2009), lutein (C40H56O2) and lycopene (C40H56). immune-modulating activities in HIV-infected patients (Sayeed The amount of α-carotene in Cryptomonas sp. and et al., 2016). While crinosterol and brassicasterol are used as anti- Hemiselmis virescens has been 0.28 and 0.1 mg/g dry weight aging factors (Sun et al., 2014), stigmasterol is often regarded as respectively (Allen et al., 1964). Cryptoxanthin, which is another the most valuable phytosterol due to its anti-inflammatory effects interesting carotenoid of cryptophytes, is intimately connected and health-promoting benefits (Gabay et al., 2010; Tang et al., to β-carotene in terms of structure, with only an addition of a 2011). Benefits of stigmasterol have been shown in the therapy of hydroxyl group. Cryptoxanthin is a member of carotenoids rheumatic diseases as an anti-stiffness factor; it also has noticeable class, which are known as xanthophylls. In the human body, anti-osteoarthritic and anti-catabolic features (Gabay et al., 2010). cryptoxanthin is converted to vitamin A (retinol) and is hence called provitamin A. Like other carotenoids, it is an antioxidant Carotenoids and can help to block free radical damage to cells and DNA, as Carotenoids are considered as the most varied and extensive well as stimulate the repair of oxidative damage to DNA pigments which are found in nature. They are lipid soluble carbon (Lorenzo et al., 2009). Recent studies suggest that compounds with a common C40 backbone structure of isoprene β-cryptoxanthin (3-hydroxy-β-carotene) could conceivably units (terpenoid). They are classified into two groups: carotenes play as a chemopreventive factor against lung cancer (Lian (hydrocarbon carotenoids, like β-caroten and lycopene) and et al., 2006). Similarly, α-carotene exhibits anti-carcinogenic xanthophylls (oxygenated carotenoids, such as lutein, and anti-diabetic activities (Sathasivam and Ki, 2018). Lutein zeaxanthin and astaxanthin) (Gong and Bassi, 2016). Thus far, and its derivatives are found only in red algae (mainly 600 different carotenoids have been identified that have various macroalgae), cryptophytes, euglenophytes, biological activities in algae, bacteria, plants and animals (Polivka chlorarachniophytes and green algae (Takaichi, 2011). It and Sundstrom, 2004). accumulates preferentially in the macula lutea (area of the Many of the effective medical and nutritional studies show retina near the optic disk that provides central vision), that the antioxidant properties of carotenoids can play a protecting the retina from oxidative damage from UVR. remarkable role in decreasing the prevalence of many diseases; Lutein can also improve skin elasticity, and has antioxidant, specifically those affected by light (Cardozo et al., 2017), as anti-inflammatory, photoprotection and anti-carcinogenic carotenoids directly create photoprotection against UV light in activities (Woodside et al., 2015). Lycopene is a rare algal the skin (Aust et al., 2005). Since carotenoids show antioxidant carotene, identified by visible and mass spectrometry and benefits and nutritional value for hair and skin, they are applied as cochromatography as a trace constituent in Cryptomonas effective ingredients with biological functions in cosmetics such as creams and lotions (Stahl and Sies, 2012). The benefits that carotenoids offer to human health are lower risk of inflammation, TABLE 3 | Cryptophyte species with the carotenoids α-carotene and alloxanthin heart disease and type 2 diabetes, cancer prevention, improved Strains α-carotene (pg cell−1) Alloxanthin (pg cell−1) eye health and protection of neurons (Novoveska et al., 2019). According to some reports, a diet rich in carotenoids is connected Chroomonas sp. 6.2 9.8 to a reduced risk of various kinds of cancers such as lung and Cryptomonas acuta 6.9 7 Cryptomonas irregularis 5.9 6.4 stomach, ocular diseases (eye diseases) like cataract and age- Cryptomonas ovata 2.7 2.8 related macular degeneration (AMD) and cardiovascular diseases Cryptomonas curvata 5.6 7.6 (Krinsky and Johnson, 2005; Moeller et al., 2006). For example, Rhodomonas falcata 3.5 3.6 astaxanthin shows anti-hypertensive properties and can influence Rhodomonas salina 0.5 0.5 the reduction of blood pressure and heart strokes in rats, whereas Storeatula sp. 4.1 4 β-carotene could prevent the activation and nuclear translocation (adapted from Cunningham et al., 2018).

Frontiers in Pharmacology | www.frontiersin.org 5 February 2021 | Volume 11 | Article 618836 Abidizadegan et al. Biomedical Applications of Cryptophyte Algae ovata (Pennington et al., 1985). The biological functions of this and may therefore provide a range of pharmaceutical applications composition include photoprotection and radioprotection related to e.g. their anti-aging, anti-Alzheimer and anti-cancer against gamma-radiation-induced cellular damages. It is also activities (Batista et al., 2006; Sonani et al., 2016). Phycoerythrin a strong antioxidant with antiradical activity. According to has been reported to have antifungal, antibacterial, antioxidant (Kong et al., 2010), lycopene performs a principal role in and dermatoprotective activities (Verma et al., 2018), whereas chronic diseases including cardiovascular disease, antibacterial, immune system modulating, anti-cancer (prostate, neurodegenerative disorders, cancer and atherosclerosis. breast and cervix), melanogenesis inhibiting and hematological roles have been reported for PC (Soni et al., 2015). Additionally, Phycobiliproteins the consumption of edible algae containing PC has health Phycobiliproteins (PBPs) are a group of colored proteins that are promoting activities including prevention of inflammation, located in phycobilisomes (PBS), and act as photosynthetically degradation of plasma lipid concentration through reduction active pigments. They can be easily extracted as pigment-protein in cholesterol absorption and inhibition of oxidative stress via complexes (Figure 3). PBPs are classified into three groups in blocking lipid peroxidation (Ku et al., 2013). In hamsters that accordance with the existence of diverse chromophores (Ducret were fed a diet supplemented with PC, fatty lesion development et al., 1998): 1) phycoerythrin (PE: λmax 480–570 nm); 2) and cardiac production of superoxide anion were considerably phycocyanin (PC: λmax 590–630 nm) and 3) allophycocyanin reduced (Riss et al., 2007). (APC: λmax 620–665 nm). Recently, numerous studies have PBPs are the major light-harvesting pigments of cryptophytes discovered bioactivities of different phycobiliproteins showing (Sidler, 1994). As cryptophytes contain one biliprotein, either PC several antioxidant and radical scavenging activities, as well as or PE (Figure 4) and no APC, the path of energy transfer is anti-inflammatory and anti-cancer activities (Stengel et al., 2011; different from red algal and cyanobacterial phycobiliproteins; in ; Ravi et al., 2015 Jiang et al., 2017). PBPs include aspects relevant the absence of allophycocyanin in cryptophytes, chlorophyll C2 in human medicine including antimicrobial, neuroprotective and acts as an intermediate between the biliprotein and chlorophyll a hepatoprotective properties (Richa et al., 2011). PBPs can provide (Hill and Rowan, 1989). The cryptophyte biliproteins are named great protection to kidney cells against oxidative stress and based on different wavelengths and their respective absorption − cellular damage created by mercuric chloride HgCl2 (Ughy maxima (e.g. phycoerythrin 545 PE545 and phycocyanin et al., 2015). They play a substantial role in the commercial 630−PC630) (Table 4). sector, as they have several applications. PBPs are widely used as The marine cryptophyte Rhodomonas and the fresh water natural pigments in numerous food and cosmetic industry cryptophyte Cryptomonas are promising candidates for the products such as jellies, dairy products, chewing gum production of PE, a red-colored PBP used as a fluorescent (Santiago-Santos et al., 2004), lipstick, sun-protecting cream probe and analytical reagent, as well as a natural dye in food, and eye shadow pallets (Sonani et al., 2016). A number of beauty products and cosmetics (Chaloub et al., 2015; studies suggest that PBPs also have health promoting abilities, Cunningham et al., 2018). Moreover, the genus Chroomonas has been reported as a great source of PC (Cunningham et al., 2018), a blue light-harvesting phycobiliprotein applied as colorant in cosmetic and with antitumor, antioxidant and anti-inflammatory activities in medicine (Liu et al., 2016). Compared with other phycobilisome containing algae, such as red algae and cyanobacteria, a significant advantage of cryptophytes is the presence of only one type of biliprotein in one species. This, together with the lack of a cell wall, makes the unit functions associated with cell disruption and downstream processing of PE easy and economically feasible (Chaloub et al., 2015). Mycosporine-like Amino Acids MAAs are a family of intracellular compounds protecting aquatic organisms against solar radiation. These UV-absorbing compounds are water soluble and low molecular weight components (<400 Da). Their chemical structure is based on either a cyclohexenone (wavelength maxima (λmax) 310 nm in λ ultraviolet-B) or cyclohexenimine ( max: 360 nm in ultraviolet-A) ring structure with amino acid substituents (Karentz et al., 1991). Biosynthesis of MAAs occurs via a branch of the shikimic acid pathway. Thus far, 20 MAAs have been identified from different Figure 3 | Schematic structure and function of phycobiliproteins in light- organisms (Carreto and Carignan, 2011), of which some harvesting. PE, Phycoerythrin; PC, Phycocyanin and APC, Allophycocyanin examples are presented in Figure 5. They are present (adapted from Heldt et al., 2011). intracellularly in many marine and freshwater organisms

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Figure 4 | Chemical structure of PE and PC (adapted from Wilk et al., 1999; Hoseini et al., 2013).

of MAAs on the skin, a study including 20 middle-age women fi TABLE 4 | Classi cation of cryptophytes based on biliprotein type and PBP reported that a cream containing 0.005% MAAs obtained from concentration. red algae can counteract UV-A effects and develop skin Genus Biliprotein Type PBP (pg cell−1) smoothness (Morone et al., 2019). Mycosporine-glycine has been reported to have proper antioxidant activity, providing Cryptopmonas PE565 or none 2.3–40.4 Rhodomonas PE545 2.6–13.9 some preservation against photooxidative stress derived by Rhinomonas 3.3 ROS (Cardozo et al., 2017). Additionally, MAAs are regarded Storeatula 14.6 as anti-cancer factors because of their anti-proliferative activities Guillardia 0.9 on neoplastic cells, and their antioxidant activities involved in the Hanusia 1.9 Plagioselmis — suppression of tumor proliferation (Chrapusta et al., 2017). The Teleaulax — anti-photoaging role of MAAs has been examined; based on Geminigera 6.6 in vitro analysis; asterina-330 can significantly decrease the lipid Proteomonas 1.2–10.3 peroxidation, which affects initiating and mediating of the aging – Hemiselmis PC615, PC630 0.2 1.6 process (Coba et al., 2009). Moreover, porphyra-334 shows PC577 or PE555 0.5 Chroomonas PC630 or PC645 6–12.2 inhibitory potential on the UV-increased activity of elastase Komma PC645 — leading to elastin decomposition and wrinkle formation (Ryu Flacomonas PC569 — et al., 2014). The microalgal-derived shinorine, mycosporine-

(adapted from Tanifuji & Onodera, 2017; Cunningham et al., 2018). glycine and porphyra-334 exhibit inhibitory effects on the expression of inflammation-related genes, hence showing anti- inflammatory potential (Rosic, 2019). (Rezanka and Temina, 2004). Although other marine organisms The photoprotective UV filtering and antioxidant role of obtain MAAs by diet and bacterial association, algae MAAs have also been supported by affirming the high biosynthesize MAAs themselves (Carroll and Shick, 1996). photostability and the release of heat to the medium as the In addition to their role as a sunscreen, MAAs act as leading pathway of the photoexcited molecules (Conde et al., antioxidants (Dunlap and Yamamoto, 1995). Skin 2007). The most comprehensive study (152 algal species) on pigmentation is an endogenous and protective structure MAAs in microalgae reported that high amounts of these against the damages resulted from high exposure to sunlight, compounds are found in dinoflagellates, cryptophytes, since melanin absorbs a broadband of UV-radiation and removes prymnesiophytes and raphidophytes (Jeffrey et al., 1999; one of the main UV-induced cellular subsequences, reactive Rezanka and Temina, 2004). In the study of (Llewellyn and oxygen species (ROS) (Brenner and Hearing, 2008). A large Airs, 2010), Rhodomonas baltica possess MAAs compounds fi λ number of UV lters are produced around the world yearly with high levels at 310 nm; the max at 310 nm is consistent due to the consumer demand for sunscreen in lotions, lipsticks, with structures of mycosporine-glutamine (M-Glu, C13H19NO8), moisturizers and facial makeup. Considering the possible impact mycosporine-taurine (M-Tau, C13H19NO8), mycosporine-serine

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Figure 5 | Chemical structure of some MAAs and their maximum absorption (λmax) (adapted from Chrapusta et al., 2017).

(M-Ser, C10H17NO7S) and mycosporine-glycine (M-Gly, These provide new insights into the application of C10H15NO6). M-Gly has been reported to have antioxidative, mycosporine-like amino acids in the cosmetic sectors. anti-inflammatory and antiaging activities (Suh et al., 2014; Ngoennet et al., 2018). M-Gly purified from macroalgae Polysaccharides Porphyra yezoensis has considerable effect on the wound Polysaccharides, especially sulfated exopolysaccharides (EPS), healing process in humans (Choi et al., 2015). Additionally, form a group of important high molecular weight biopolymers M-Tau with antioxidant activity exhibits efficient protective released from microorganisms like microalgae into the ability toward cell damaged by ROS (Zhang et al., 2007). environment during their growth (Liu et al., 2016). Evaluation

Frontiers in Pharmacology | www.frontiersin.org 8 February 2021 | Volume 11 | Article 618836 Abidizadegan et al. Biomedical Applications of Cryptophyte Algae of structures, compositions, functions and characteristics of EPS TABLE 5 | Carbohydrate composition and total polysaccharide of C. are necessary for understanding their production mechanism and tetrapyrenoidosa and C. obovata. attributes for promising applications. The primary compositions C. tetrapyrenoidosa C. obovata of EPS contain lipids, polysaccharides, nucleic acids (DNA) and Carbohydrate % Total polysaccharide proteins. Various factors such as nutrient availability, strain, composition (%) species and physiology affect diversity of polymers in EPS and Fraction 1 Fraction 2 the numbers of particular compounds (Xiao and Zheng, 2016). They act as antiviral factors, health foods and antioxidants. They Rhamnose 9.0 0.8 15.3 present anti-inflammatory properties, drag-reducing substances Fucose 24.3 8.6 41.6 Xylose 4.7 0.4 2.7 and play a considerable role in the immunomodulatory system Mannose 15.4 0.8 3.6 (Raposo et al., 2013). Galactose 13.7 36.0 4.4 Most algal polysaccharides (agars, carrageenans, alginates) Glucose 3.5 0.5 2.1 used in different industries are gained from macroalgae. Glucuronic acid 4.1 47.0 4.3 N-acetyl galactosamine 8.6 0.27 26.9 However, it has been shown that the polysaccharides from some marine microalgae show antiviral bioactivity against (adapted from Giroldo et al., 2005; Giroldo & Vieira, 2002). various kinds of viruses, including mammalian viruses (Radonic et al., 2010). Investigations of sulfated cruentum, the cyanobacterium Spirulina, and the cryptophyte polysaccharides (sPS) from marine microalgae, especially ones Chroomonas have already shown potential for commercial produced by the red microalga Porphyridium, report the antiviral exploitation (Nie et al., 2002; Bermudez et al., 2004; Keidan activity of sPS. The mechanisms of activity are not yet entirely et al., 2009). understood, but can relate to the anionic nature of the sPS. Reports of EPS production and characterization of Sulfate polysaccharides are able to prohibit infection by cryptophytes is rare. There is a handful of articles on this different viruses via preventing infiltration of viral particles topic, and only few of them show profiling results. However, into host cells. However, there are also other mechanisms, the profiling of the EPS secreted by a tropical cryptophyte, such as the restriction of binding/adsorption, or even Cryptomonas tetrapyrenoidosa, has been made for two duplication throughout the early phases of the virus cycle, different fractions isolated by anion exchange chromatography which may be involved in the antiviral activities of sPS (Table 5)(Giroldo et al., 2005). In that study, Fraction 1 eluted (Raposo et al., 2014). with 0.5 M NaCl while Fraction 2 eluted with 1.0 M NaCl. In addition to their function as dietary fiber, sulfated Fraction 1 had fucose, galactose, N-acetyl glucosamine and polysaccharides secreted from microalgae have the ability to mannose as the main components, whereas galactose and protect systems against oxidative and radical stress factors by glucuronic acid were the main EPSs in Fraction 2. prohibiting the activity and accumulation of reactive chemical Additionally, the EPS of Cryptomonas obovata (also a tropical species and free radicals (Sun et al., 2009). Polysaccharides from strain) has been described (Table 5)(Giroldo et al., 2005). The marine microalgae, including Porphyridium, Phaeodactylum and EPS profiles were generally similar between the two strains, but Chlorella stigmatophora, have shown pharmacological attributes, the proportions were quite distinct. The main EPS of C. obovata like anti-inflammatory effects, and function as was the sulfated fucose-rich polysaccharide; this strain was also immunomodulatory factors. Studies have proven the direct rich in N-acetyl galactosamine (GlcNAc; Table 5). Studies stimulating significance of Phaeodactylum tricornutum on the indicate that fucose-containing sulfated polysaccharides from immune cells by the positive phagocytic activity (Guzman et al., algae potentially act as skin-cancer preventive factors (Ale 2003). One notable feature of polysaccharides is the potentiality et al., 2011) and a strong anticoagulant (Raposo et al., 2015). to suppress tumor cell growth. The homopolysaccharide of N-acetyl galactosamine can have cytoprotective activities to Gymnodinium impudicum with its immunomodulatory restore the integrity and normal operation of the mucous properties prevented the growth of tumor cells, both in vitro membrane in humans, and act as an inexpensive and non- and in vivo (Yim et al., 2004). In a recent study (Gardeva et al., toxic treatment for inflammatory bowel disease (Chen et al., 2014), intense anti-tumour activity has been reported by the 2010). Moreover, GlcNAc can improve skin health by increasing polysaccharide of Porphyridium cruentum. This sulfated polymer the proliferation and collagen expression of skin fibroblasts (Chen effectively controlled Graffi myeloid tumor division in vitro and et al., 2008), in addition to its moisturizing properties (Bissett in vivo. Polysaccharides have immunostimulating effects that et al., 2007). Finally, polysaccharides such as rhmanose, xylose, cause inhabitation of tumor cell activity. For example, EPS glucose and glucuronic acid derived from these cryptophytes have from Porphyridium has potential as an anticancer agent that had antioxidant, antibacterial, antiviral, antilipidemic, inhibits the growth of different cancer cell lines (Gardeva et al., antiglycemic and infection prevention potential (Raposo et al., 2014). EPS from unicellular algae are also considered as possible 2015). candidates in reducing coronary heart disease because of their hypocholesterolaemic effects (Dvir et al., 2009), anti-adhesive and Vitamins anti-inflammatory activities, prevention of tumor cell growth and Vitamins - vital organic micronutrients - cannot be directly immunomodulatory effects (Raposo et al., 2015). The production synthesized by animals in sufficient quantities. Therefore, of sulfated exopolysaccharides from the red microalga P. animals must gain them from external sources. These

Frontiers in Pharmacology | www.frontiersin.org 9 February 2021 | Volume 11 | Article 618836 Abidizadegan et al. Biomedical Applications of Cryptophyte Algae compounds are necessary for urgent metabolic functions, and act Due to their therapeutic functions, phenolic compounds have as precursors for essential enzyme cofactors (Weels et al., 2017). recently gained the interest of consumers and functional food Microalgae are an unexplored source of almost all kinds of manufactures. Extracted phenolic compounds show a vast array vitamins including pro-vitamin A (α- and β-carotene, of activities, such as anti-radical, UV-protection and anti-HIV, apocarotenoids), vitamin C (ascorbic acid), vitamin E and they act as inhibitors of melanin formation. They also have (tocopherols and tocotrienols), vitamin D, and some vitamins been reported to have anti-adipogenic activities, and of the B group (particularly B1 and B12)(Uribe et al., 2017; neuroprotective effects, and a potential treatment of Galasso et al., 2019). Natural and synthetic retinoids (a class of Alzheimer’s disease (Stengel et al., 2011). An extensive review compounds including vitamin A and the main apocarotenoid (Cornish and Garbary, 2010) shows the promising applications of produced in algae) have been mainly represented in preventing polyphenols, including algae as antioxidants, in human health the growth and development of various sorts of tumors, including and nutrition. Food that is rich in antioxidants has been skin, breast, oral, lung, prostatic and bladder cancers (Altucci and supported to prevent cardiovascular disease (CVD) that Gronemeyer, 2001; Jonas et al., 2015). Vitamin C shows valuable represent a multiprocess disorder including oxidative stress, health effects, such as cancer and atherosclerosis prevention, and inflammatory dysfunction, and vascular remodeling. A clear serves as an immunomodulatory agent, for instance for the association between the consumption of seaweed by Japanese prohibition of tuberculosis (Nunes-Alves et al., 2014). people and reducing risk of mortality by CVDs has also been According to studies, vitamin C has a significant effect on the detected (Shimazu et al., 2007). Further, polyphenols extracted prevention of gastric cancer (Granger and Eck, 2018). Vitamin D from the brown macroalga Ecklonia sp. reduced UVB-induced plays an important role in a vital process of calcium absorption skin tumor improvement in mice notwithstanding whether the and metabolism for bone health and homeostasis, and it is polyphenols were used topically or as a dietary component, beneficial in cancer prevention and anti-neurodegenerative suggesting that the activity of these algae-based antioxidants is effects. This vitamin also regulates calcium and phosphate uninfluenced by digestive processes (Hwang et al., 2006). metabolism and is essential for maintaining bone health, i.e. Phlorotannins, a type of tannins that are a class of astringent, for preventing osteomalacia and osteoporosis (Feldman et al., polyphenolic biomolecules, have been detected to have repressive 2014). Vitamin E inhibits lipoprotein oxidation processes that effects on HIV-1 reverse transcriptase activity, which means that have a role in the growth of cancer in mice. Furthermore, it they can fight against human immunodeficiency viruses (Ahn improves endothelial function and reduces vascular damage et al., 2004). They also involve in the development of anti-allergic (Corina et al., 2019). High levels of Vitamin B12 are attributed compounds similar to phlorofucofuroeckol-B, which show an to reduced risk of breast cancer, and can act on DNA repair and impact on histamine release (Sugiura et al., 2007), and has a histone methylation (Gruber, 2016). protective effect against diabetes (Lee and Jeon, 2013). The green microalga Dunaliella tertiolecta has vitamin B12,B2, Additionally, they protect cells from radiation-induced injury E and provitamin A. Moreover, the green microalga Tetraselmis (Shin et al., 2014), which is another indication of their efficacy in suecica is a potential source of vitamin B1,B3,B5,B6, and C anti-oxidative protection. (Fabregas and Herrero, 1990). Chlorella species have generally Several classes of flavonoids, such as isoflavones, flavanones, fl been detected to contain vitamin B7 in high concentrations, and avonols, and dihydrochalcones are found in microalgae around 9–18% of Chlorella strains have been reported to contain (Manach et al., 2004). Flavonoids contain a broad spectrum of vitamin B12 (Koyande et al., 2019). Chlorella and Spirulina health-promoting effects and are fundamental components in a contain high concentrations of B9 (folic acid), a principal diversity of nutraceutical, pharmaceutical, medicinal and vitamin to cell formation and bone and teeth development. cosmetic applications (Andrade et al., 2018). Flavonoid-rich Further, B9 maintains normal metabolism and preservation of foods have been shown to have about 50% reduction in the skin membranes (Becker, 2007). The amount of vitamin C varies risk of dementia, a delay in the Alzheimer’s disease and decrease in algae, and a study on algal species reported a significant the risk of developing Parkinson’s disease (Vauzour et al., 2010). amount of vitamin C (C6H8O6) in the cryptophyte Accordingly, the potential pharmaceutical applications of algal − Cryptomonas maculata (6.45 pg cell 1)(Brown and Miller, polyphenols have been widely investigated because of their anti- fl 1992). Thiamine (B1,C12H17N4OS+) concentration in the cancer, photo-aging preventing and anti-in ammatory effects cryptophyte Rhodomonas salina has been shown to be about (Thomas and Kim, 2011; Li et al., 2014; Machu et al., 2015). −1 fi fl 358.8 nmol g cell (Sylvander et al., 2013). However, A speci c class of avonoids, 2-styrylchromones (2-SC, C17 cryptophytes are not reported to be rich in other vitamins. H12 O2), was extracted from the marine cryptophyte Chrysophaeum taylori in 1986 by W. H. Gerwick (Gomes Phenolic Compounds et al., 2010). Certain analogues of these components have been Phenolic compounds are secondary metabolites and, due to their high synthesized and assessed in biological systems, showing that both production under stress in organisms, are frequently identified as the natural and synthetic compounds possess a myriad of stress compounds. Phenolics have chemical protecting mechanisms biological activities (Table 6) including anti-allergic, anti- against UV radiation (Coba et al., 2009) and metal contamination tumor (Li et al., 2007), antioxidant, antimicrobial, antiviral, (Connan and Stengel, 2011). Chemically, polyphenols are classified anti-inflammatory (Madhava Rao et al., 2016), antifungal, into several classes, such as phenolic acids, flavonoids, isoflavonoids, hepatoprotective (Pinto et al., 2015), anti-infective, immune stilbenes, lignans, and phenolic polymers (Ozcan et al., 2014). system promoting and skin protective from UV radiation

Frontiers in Pharmacology | www.frontiersin.org 10 February 2021 | Volume 11 | Article 618836 Abidizadegan et al. Biomedical Applications of Cryptophyte Algae

TABLE 6 | Some biological activities of 2-styrylchromones.

Biological activity Specific effect (s) Chemical structure

Antiallergenic Inhibition of histamine release from passively sensitized rat peritoneal cells

Antitumor Cytotoxicity to tumor cell lines

Tumor-specific cytotoxic effect and tumor-specific antiproliferative effect

Antiproliferative effect against human carcinoma cell lines

Antiviral Activity against human rhinoviruses (HRV)

Antioxidant Protective activity against the tert-butylhydroperoxide from proxidant hepatotoxicity in rat hepatocytes and scavenging impact of ROS and reactive nitrogen species

Anti-inflammatory Inhibition of COX-1 activity

Inhibition of LTB4 production in human neutrophils

(adapted from Gomes et al., 2010).

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(Gomes et al., 2010; Tungmunnithum et al., 2018). This clearly so compared to many of the already commercially employed demonstrates the ability of cryptophytes to produce complex algae, they are easier to break and process more for commercial phenolic compounds. Characterization, recognition and purposes, which also promotes the use of these exceptional algae. exploration of phenolic compounds in microalgae is The review highlights the importance of bioactive indispensable, specifically since they may possess unique compounds derived from cryptophyte algae for medical, phenolic compounds (Safafar et al., 2015). pharmaceutical, cosmeceutical and food sciences, and it aims to provide new directions for future research. There is little literature associated with cryptophytes, their bioactive CONCLUSION AND FUTURE components and their functions. In future, further research is PERSPECTIVES needed on the isolation of various bioactive compounds and their efficiency from a growing number of cryptophyte strains. Microalgae offer a promising source of various protective and There is also the need to compare the cryptophyte results with bioactive compounds, which could help protect humans as well as information gathered from other algal species. Furthermore, it the environment. Cryptophytes are productive in suitable growth is essential to determine the optimal growth conditions for the conditions, and are biologically active and chemically unique, extraction of high quality and sustainable bioactive thus representing secondary metabolites that could be widely compounds for commercial use. used in nutraceuticals, cosmetics and pharmaceuticals. Therefore, they could be used in biomedical applications to maintain or recover human health. The chemical composition of algae is AUTHOR CONTRIBUTIONS genetically determined, and not all species are capable of producing all compounds. Cryptophytes are fully packed with MA collected sources and wrote the manuscript, designed the bioactive compounds; they are extremely rich in ω-3 PUFA, figures and Tables. EP and JB contributed to the conception and especially in EPA and DHA, as well as in phytosterols. design of the article and revised it critically for important Moreover, they have high-value pigments, i.e. carotenoids and intellectual content. PBPs. They offer, as yet, nearly unexplored source of EPS, vitamins and phenolic compounds with several antioxidant, anti-inflammatory, anti-cancer, anti-Alzheimer’s and other ACKNOWLEDGMENTS health-promoting effects. Due to their exceptional chemical composition, cryptophytes are already proven to be The authors would like to thank Janne-Markus Rintala for particularly important food sources in aquatic ecosystems. providing the cryptophyte photo and Language Center of the However, this potential group of algae is nearly untapped in University of Helsinki for editing the English of this biotechnology. Cryptophytes do not have a recalcitrant cell wall, manuscript.

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Frontiers in Pharmacology | www.frontiersin.org 16 February 2021 | Volume 11 | Article 618836 Abidizadegan et al. Biomedical Applications of Cryptophyte Algae

Xiao, R., and Zheng, Y. (2016). Overview of microalgal extracellular polymeric Conflict of Interest: The authors declare that the research was conducted in the substances (EPS) and their applications. Biotechnol. Adv. 34, 1225–1244. doi:10. absence of any commercial or financial relationships that could be construed as a 1016/j.biotechadv.2016.08.004 potential conflict of interest. Yim, J. H., Son, E., Pyo, S., and Lee, H. K. (2004). Novel sulfated polysaccharide derived from red-tide microalga Gyrodinium impudicum strain KG03 with Copyright © 2021 Abidizadegan, Peltomaa and Blomster. This is an open-access immunostimulating activity in vivo. Mar. Biotechnol. 7, 331–338. doi:10.1007/ article distributed under the terms of the Creative Commons Attribution License (CC s10126-004-0404-6 BY). The use, distribution or reproduction in other forums is permitted, provided the Zhang, L., Li, L., and Wu, Q. (2007). Protective effects of mycosporine-like amino original author(s) and the copyright owner(s) are credited and that the original acids of Synechocystis sp. PCC 6803 and their partial characterization. publication in this journal is cited, in accordance with accepted academic practice. J. Photochem. Photobiol. B Biol. 86, 240–245. doi:10.1016/j.jphotobiol.2006. No use, distribution or reproduction is permitted which does not comply with 10.006 these terms.

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